title: Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen.
abstract: Despite presence of circulating retina-specific T cells in healthy individuals, ocular immune privilege usually averts development of autoimmune uveitis. To study the breakdown of immune privilege and development of disease, we generated transgenic (Tg) mice that express a T cell receptor (TCR) specific for interphotoreceptor retinoid-binding protein (IRBP), which serves as an autoimmune target in uveitis induced by immunization. Three lines of TCR Tg mice, with different levels of expression of the transgenic R161 TCR and different proportions of IRBP-specific CD4⁺ T cells in their peripheral repertoire, were successfully established. Importantly, two of the lines rapidly developed spontaneous uveitis, reaching 100% incidence by 2 and 3 months of age, respectively, whereas the third appeared "poised" and only developed appreciable disease upon immune perturbation. Susceptibility roughly paralleled expression of the R161 TCR. In all three lines, peripheral CD4⁺ T cells displayed a naïve phenotype, but proliferated in vitro in response to IRBP and elicited uveitis upon adoptive transfer. In contrast, CD4⁺ T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells that appeared to have been peripherally converted from conventional CD4⁺ T cells rather than thymically derived. Thus, R161 mice provide a new and valuable model of spontaneous autoimmune disease that circumvents the limitations of active immunization and adjuvants, and allows to study basic mechanisms involved in maintenance and breakdown of immune homeostasis affecting immunologically privileged sites such as the eye.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA. hreiko@mail.nih.gov
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Agarwal
authors.forename: Wai Po
authors.initials: WP
authors.lastname: Chong
authors.forename: Yingyos
authors.initials: Y
authors.lastname: Jittayasothorn
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mattapallil
authors.forename: Sonia
authors.initials: S
authors.lastname: Nguyen
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Rafael
authors.initials: R
authors.lastname: Villasmil
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Zaruhi
authors.initials: Z
authors.lastname: Karabekian
authors.forename: Simon D
authors.initials: SD
authors.lastname: Lytton
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005136:Eye Proteins / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology*; D012160:Retina / Q000276:immunology*; D012177:Retinol-Binding Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D001324:Autoantigens; D016207:Cytokines; D005136:Eye Proteins; D011948:Receptors, Antigen, T-Cell; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial
keywords: AIRE; Ag; Autoimmune uveitis; CFA; EAU; HEL; IRBP; Immune privilege; PMA; RAG; SP; Spontaneous disease; T cell receptor; TCR; TCR transgenic mouse; WT; antigen; autoimmune regulator; complete Freund's adjuvant; experimental autoimmune uveitis; hen egg lysozyme; interphotoreceptor retinoid binding protein; phorbol myristate acetate; recombination activating gene; single positive; wild type